US7514565B2 - 3,5-Difluoropyridines - Google Patents
3,5-Difluoropyridines Download PDFInfo
- Publication number
- US7514565B2 US7514565B2 US11/639,955 US63995506A US7514565B2 US 7514565 B2 US7514565 B2 US 7514565B2 US 63995506 A US63995506 A US 63995506A US 7514565 B2 US7514565 B2 US 7514565B2
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- United States
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- alkyl
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- radical
- formula
- carbon atoms
- Prior art date
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- WRXAZPPGFLETFR-UHFFFAOYSA-N 3,5-difluoropyridine Chemical class FC1=CN=CC(F)=C1 WRXAZPPGFLETFR-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- 150000003839 salts Chemical class 0.000 claims description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 46
- -1 trifluoromethoxy, carboxyl Chemical group 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 30
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 30
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 28
- 125000004432 carbon atom Chemical group C* 0.000 description 24
- 239000000203 mixture Substances 0.000 description 23
- 239000001257 hydrogen Substances 0.000 description 22
- 229910052739 hydrogen Inorganic materials 0.000 description 22
- 150000003254 radicals Chemical group 0.000 description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 20
- 238000000034 method Methods 0.000 description 19
- 210000004027 cell Anatomy 0.000 description 18
- 229940093499 ethyl acetate Drugs 0.000 description 18
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 16
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 description 14
- 235000019439 ethyl acetate Nutrition 0.000 description 14
- 125000004076 pyridyl group Chemical group 0.000 description 14
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 14
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 13
- 125000001424 substituent group Chemical group 0.000 description 13
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 12
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 12
- 239000000243 solution Substances 0.000 description 12
- 0 [1*]C1N=C([5*])N([4*])C([3*])=C1C([2*])=O Chemical compound [1*]C1N=C([5*])N([4*])C([3*])=C1C([2*])=O 0.000 description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 239000000460 chlorine Substances 0.000 description 8
- 229910052801 chlorine Inorganic materials 0.000 description 8
- 229910052736 halogen Inorganic materials 0.000 description 8
- 150000002367 halogens Chemical group 0.000 description 8
- 125000004454 (C1-C6) alkoxycarbonyl group Chemical group 0.000 description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 7
- 108020004414 DNA Proteins 0.000 description 7
- 125000004122 cyclic group Chemical group 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 description 6
- ATUOLSDAAPMVJJ-UHFFFAOYSA-N 3,5-dichloropyridine-2-carbonitrile Chemical compound ClC1=CN=C(C#N)C(Cl)=C1 ATUOLSDAAPMVJJ-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- KUNKHBQPUQEYFO-UHFFFAOYSA-N [H]N1C(C2=NC=CC=C2F)=NC(C2=C(Cl)C=C(F)C=C2)C(C(=O)OCC)=C1C Chemical compound [H]N1C(C2=NC=CC=C2F)=NC(C2=C(Cl)C=C(F)C=C2)C(C(=O)OCC)=C1C KUNKHBQPUQEYFO-UHFFFAOYSA-N 0.000 description 6
- QXBCQKSAVAGJEJ-UHFFFAOYSA-N [H]N1C(C2=NC=CC=C2F)=NC(C2=C(Cl)C=CC=C2)C(C(=O)OCC)=C1C Chemical compound [H]N1C(C2=NC=CC=C2F)=NC(C2=C(Cl)C=CC=C2)C(C(=O)OCC)=C1C QXBCQKSAVAGJEJ-UHFFFAOYSA-N 0.000 description 6
- 229960000583 acetic acid Drugs 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 6
- 125000004093 cyano group Chemical group *C#N 0.000 description 6
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- WDLIDNANRSUVFL-UHFFFAOYSA-N 3,5-difluoropyridine-2-carboximidamide;hydrochloride Chemical compound Cl.NC(=N)C1=NC=C(F)C=C1F WDLIDNANRSUVFL-UHFFFAOYSA-N 0.000 description 5
- 230000000840 anti-viral effect Effects 0.000 description 5
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 208000002672 hepatitis B Diseases 0.000 description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 5
- 238000010992 reflux Methods 0.000 description 5
- 239000006228 supernatant Substances 0.000 description 5
- 238000011282 treatment Methods 0.000 description 5
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 description 4
- DUKJVWUITYUNPT-UHFFFAOYSA-N 3,5-difluoropyridine-2-carboximidamide Chemical compound NC(=N)C1=NC=C(F)C=C1F DUKJVWUITYUNPT-UHFFFAOYSA-N 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 4
- QEXZNICOVYJLCW-UHFFFAOYSA-N C.CCOC Chemical compound C.CCOC QEXZNICOVYJLCW-UHFFFAOYSA-N 0.000 description 4
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 4
- 150000001299 aldehydes Chemical class 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 150000001409 amidines Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 4
- 229910052794 bromium Inorganic materials 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 238000009396 hybridization Methods 0.000 description 4
- FVNJBPMQWSIGJK-UHFFFAOYSA-N methyl 4-(2-chloro-4-fluorophenyl)-2-(3,5-difluoropyridin-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate Chemical compound COC(=O)C1=C(C)NC(C=2C(=CC(F)=CN=2)F)=NC1C1=CC=C(F)C=C1Cl FVNJBPMQWSIGJK-UHFFFAOYSA-N 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000008194 pharmaceutical composition Substances 0.000 description 4
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 description 4
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- 125000001425 triazolyl group Chemical group 0.000 description 4
- LEIMLDGFXIOXMT-UHFFFAOYSA-N trimethylsilyl cyanide Chemical compound C[Si](C)(C)C#N LEIMLDGFXIOXMT-UHFFFAOYSA-N 0.000 description 4
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 description 3
- WLBIFECTHKFYKV-UHFFFAOYSA-N 3,5-difluoropyridine-2-carbonitrile Chemical compound FC1=CN=C(C#N)C(F)=C1 WLBIFECTHKFYKV-UHFFFAOYSA-N 0.000 description 3
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 3
- MXMFCZRMTVZSEU-UHFFFAOYSA-N CC1=C2C=C(C3=CC=CC=C3)C=NC2=CC=C1.CC1=C2C=CC=CC2=CN=C1.CC1=C2N=C(C3=CC=CC=C3)SC2=CC=C1 Chemical compound CC1=C2C=C(C3=CC=CC=C3)C=NC2=CC=C1.CC1=C2C=CC=CC2=CN=C1.CC1=C2N=C(C3=CC=CC=C3)SC2=CC=C1 MXMFCZRMTVZSEU-UHFFFAOYSA-N 0.000 description 3
- WRPCXCVNNCPSGH-UHFFFAOYSA-N COC(=O)C1=C(C)NC(C2=C(F)C=CC=N2)=NC1C1=CC=C(F)C=C1 Chemical compound COC(=O)C1=C(C)NC(C2=C(F)C=CC=N2)=NC1C1=CC=C(F)C=C1 WRPCXCVNNCPSGH-UHFFFAOYSA-N 0.000 description 3
- OPFTUNCRGUEPRZ-QLFBSQMISA-N Cyclohexane Natural products CC(=C)[C@@H]1CC[C@@](C)(C=C)[C@H](C(C)=C)C1 OPFTUNCRGUEPRZ-QLFBSQMISA-N 0.000 description 3
- 241000700721 Hepatitis B virus Species 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 3
- 239000004677 Nylon Substances 0.000 description 3
- 108020005202 Viral DNA Proteins 0.000 description 3
- 241000700605 Viruses Species 0.000 description 3
- MAXRIHYJXIGRCF-UHFFFAOYSA-N [H]N1C(C2=C(F)C=CC=N2)=NC(C2=CC=C(Cl)C=C2)C(C(=O)OCC)=C1C Chemical compound [H]N1C(C2=C(F)C=CC=N2)=NC(C2=CC=C(Cl)C=C2)C(C(=O)OCC)=C1C MAXRIHYJXIGRCF-UHFFFAOYSA-N 0.000 description 3
- YDMATUUDUCCXCD-UHFFFAOYSA-N [H]N1C(C2=NC=C(Cl)C=C2)=NC(C2=C(Cl)C=CC=C2)C(C(=O)OC)=C1C Chemical compound [H]N1C(C2=NC=C(Cl)C=C2)=NC(C2=C(Cl)C=CC=C2)C(C(=O)OC)=C1C YDMATUUDUCCXCD-UHFFFAOYSA-N 0.000 description 3
- OUSDHQZVEOFNMT-UHFFFAOYSA-N [H]N1C(C2=NC=CC=C2Cl)=NC(C2=C(F)C=C(Br)C=C2)C(C(=O)OCC)=C1C Chemical compound [H]N1C(C2=NC=CC=C2Cl)=NC(C2=C(F)C=C(Br)C=C2)C(C(=O)OCC)=C1C OUSDHQZVEOFNMT-UHFFFAOYSA-N 0.000 description 3
- JCAJYIMKCNOCGC-HNNXBMFYSA-N [H]N1C(C2=NC=CC=C2Cl)=N[C@@H](C2=C(Cl)C=C(F)C=C2)C(C(=O)OC)=C1C Chemical compound [H]N1C(C2=NC=CC=C2Cl)=N[C@@H](C2=C(Cl)C=C(F)C=C2)C(C(=O)OC)=C1C JCAJYIMKCNOCGC-HNNXBMFYSA-N 0.000 description 3
- YIOMQNRKYCNRNN-UHFFFAOYSA-N [H]N1C(C2=NC=CC=C2F)=NC(C2=C(C(F)(F)F)C=CC=C2)C(C(=O)OC)=C1C Chemical compound [H]N1C(C2=NC=CC=C2F)=NC(C2=C(C(F)(F)F)C=CC=C2)C(C(=O)OC)=C1C YIOMQNRKYCNRNN-UHFFFAOYSA-N 0.000 description 3
- UWIKZJIZSLFIRZ-UHFFFAOYSA-N [H]N1C(C2=NC=CC=C2F)=NC(C2=C(Cl)C=C(F)C=C2)C(C(=O)OC)=C1C Chemical compound [H]N1C(C2=NC=CC=C2F)=NC(C2=C(Cl)C=C(F)C=C2)C(C(=O)OC)=C1C UWIKZJIZSLFIRZ-UHFFFAOYSA-N 0.000 description 3
- 235000019270 ammonium chloride Nutrition 0.000 description 3
- 150000003863 ammonium salts Chemical class 0.000 description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 description 3
- 125000000753 cycloalkyl group Chemical group 0.000 description 3
- 231100000433 cytotoxic Toxicity 0.000 description 3
- 230000001472 cytotoxic effect Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000000706 filtrate Substances 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 description 3
- 229920001778 nylon Polymers 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 125000003386 piperidinyl group Chemical group 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 description 2
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 description 2
- 125000006823 (C1-C6) acyl group Chemical group 0.000 description 2
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 description 2
- WCFAPJDPAPDDAQ-UHFFFAOYSA-N 1,2-dihydropyrimidine Chemical class C1NC=CC=N1 WCFAPJDPAPDDAQ-UHFFFAOYSA-N 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QVGBDRDOWKIYHK-UHFFFAOYSA-N 3-fluoro-1-oxidopyridin-1-ium Chemical compound [O-][N+]1=CC=CC(F)=C1 QVGBDRDOWKIYHK-UHFFFAOYSA-N 0.000 description 2
- VZFPSCNTFBJZHB-UHFFFAOYSA-N 3-fluoropyridine-2-carbonitrile Chemical compound FC1=CC=CN=C1C#N VZFPSCNTFBJZHB-UHFFFAOYSA-N 0.000 description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 2
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- 239000007832 Na2SO4 Substances 0.000 description 2
- BHHGXPLMPWCGHP-UHFFFAOYSA-N Phenethylamine Chemical compound NCCC1=CC=CC=C1 BHHGXPLMPWCGHP-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 2
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- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- IMBKASBLAKCLEM-UHFFFAOYSA-L ferrous ammonium sulfate (anhydrous) Chemical compound [NH4+].[NH4+].[Fe+2].[O-]S([O-])(=O)=O.[O-]S([O-])(=O)=O IMBKASBLAKCLEM-UHFFFAOYSA-L 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000005484 gravity Effects 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 208000005252 hepatitis A Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
- 235000019514 herring Nutrition 0.000 description 1
- 125000001072 heteroaryl group Chemical group 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 201000002250 liver carcinoma Diseases 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- YZMHQCWXYHARLS-UHFFFAOYSA-N naphthalene-1,2-disulfonic acid Chemical compound C1=CC=CC2=C(S(O)(=O)=O)C(S(=O)(=O)O)=CC=C21 YZMHQCWXYHARLS-UHFFFAOYSA-N 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000002085 persistent effect Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- RAIYODFGMLZUDF-UHFFFAOYSA-N piperidin-1-ium;acetate Chemical compound CC([O-])=O.C1CC[NH2+]CC1 RAIYODFGMLZUDF-UHFFFAOYSA-N 0.000 description 1
- 239000002985 plastic film Substances 0.000 description 1
- 229920006255 plastic film Polymers 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 235000019446 polyethylene glycol 8000 Nutrition 0.000 description 1
- 229940085678 polyethylene glycol 8000 Drugs 0.000 description 1
- 229920000151 polyglycol Polymers 0.000 description 1
- 239000010695 polyglycol Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004742 propyloxycarbonyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 108700004121 sarkosyl Proteins 0.000 description 1
- 229930195734 saturated hydrocarbon Natural products 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 description 1
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/84—Nitriles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention relates to novel dihydropyrimidine compounds, to processes for their preparation and to their use as medicaments, in particular for the treatment and prophylaxis of hepatitis B.
- cycloalkyl having 3 to 6 carbon atoms or (C 3 -C 6 )-cycloalkyl represents cyclopropyl, cyclopentyl, cyclobutyl or cyclohexyl. Preference is given to cyclopentyl or cyclohexyl.
- Aryl generally represents an aromatic radical having 6 to 10 carbon atoms.
- Preferred aryl radicals are phenyl and naphthyl.
- (C 1 -C 6 )-acyl represents a straight-chain or branched acyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched acyl radical having 1 to 4 carbon atoms. Particularly preferred acyl radicals are acetyl and propionyl.
- (C 1 -C 6 )-alkyl represents a straight-chain or branched alkyl radical having 1 to 6 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, tert-butyl, n-pentyl and n-hexyl.
- (C 2 -C 6 )-alkenyl represents a straight-chain or branched alkenyl radical having 2 to 5 carbon atoms. Preference is given to a straight-chain or branched alkenyl radical having 3 to 5 carbon atoms. Examples which may be mentioned are: ethenyl, propenyl, alkyl, n-pentenyl and n-hexenyl.
- (C 1 -C 6 )-alkoxy represents a straight-chain or branched alkoxy radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxy radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxy, ethoxy and propoxy.
- (C 1 -C 6 )-alkylthio represents a straight-chain or branched alkylthio radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkylthio radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methylthio, ethylthio and propylthio.
- (C 1 -C 6 )-alkoxycarbonyl represents a straight-chain or branched alkoxycarbonyl radical having 1 to 6 carbon atoms. Preference is given to a straight-chain or branched alkoxycarbonyl radical having 1 to 4 carbon atoms. Examples which may be mentioned are: methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl.
- a straight-chain, branched or cyclic, saturated or unsaturated (C 1 -C 8 )-hydrocarbon radical includes, for example, the above-described (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl or (C 3 -C 6 )-cycloalkyl, preferably (C 1 -C 6 )-alkyl.
- the compounds according to the invention may exist in stereoisomeric forms which are related either as image and mirror image (enantiomers), or which are not related as image and mirror image (diastereomers).
- the invention relates both to the enantiomers or diastereomers and to their respective mixtures.
- the racemic forms can, just like the diastereomers, be separated in a known manner into the stereoisomerically pure constituents.
- the compounds of the present invention include the isomers of the general formulae (I) and (Ia) and mixtures thereof. If R 4 is hydrogen, the isomers (I) and (Ia) exist in a tautomeric equilibrium:
- the substances according to the invention may also be present as salts.
- preference is given to physiologically acceptable salts.
- Physiologically acceptable salts can be salts of the compounds according to the invention with inorganic or organic acids.
- inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid
- organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
- Physiologically acceptable salts can also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts, and also to ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
- ammonium salts which are derived from ammonia, or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
- R 5 represents 2-pyridyl which can be substituted by 1 to 2 fluorine atoms.
- Solvents which are suitable for all process variants A, B, C and D are all inert organic solvents. These preferably include alcohols, such as ethanol, methanol, isopropanol, ethers, such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether or glacial acetic acid, dimethyl formamide, dimethyl sulphoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.
- alcohols such as ethanol, methanol, isopropanol
- ethers such as dioxane, diethyl ether, tetrahydrofuran, glycol monomethyl ether, glycol dimethyl ether or glacial acetic acid, dimethyl formamide, dimethyl sulphoxide, acetonitrile, pyridine and hexamethylphosphoric triamide.
- reaction temperatures can be varied within a relatively wide range. In general, the reaction is carried out between 20 and 150° C., but preferably at the boiling point of the solvent in question.
- the reaction can be carried out at atmospheric pressure, or else at elevated pressure. In general, the reaction is carried out at atmospheric pressure.
- reaction can be carried out with or without addition of base or acid; however, it has been found that a reaction according to the invention is preferably carried out in the presence of relatively weak acids, such as, for example, acetic acid or formic acid.
- relatively weak acids such as, for example, acetic acid or formic acid.
- aldehydes of the general formula (II) used as starting materials are known or can be prepared by methods known from the literature (cf. T. D. Harris and G. P. Roth, J. Org. Chem. 44, 146 (1979), German Offenlegungsschrift 2 165 260, July 1972, German Offenlegungsschrift 2 401 665, July 1974, Mijano et al., Chem. Abstr. 59, (1963), 13 929 c, E. Adler and H.-D. Becker, Chem. Scand. 15, 849 (1961), E. P. Papadopoulos, M. Mardin and Ch. Issidoridis, J. Org. Chem. Soc. 78, 2543 (1956)).
- the ylidene- ⁇ -keto esters of the formula (V) used as starting materials can be prepared by methods known from the literature [cf. G. Jones, “The Knoevenagel Condensation”, in Organic Reactions, Vol. XV, 204 ff. (1967)].
- the enaminocarboxylic esters of the formula (VI) and the imino ethers of the general formula (VII) used as starting materials are known or can be prepared by methods known from the literature [cf. S. A. Glickman and A. C. Cope, J. Am. Chem. Soc. 67, 1017 (1945)].
- ⁇ -ketocarboxylic esters of the general formula (IV) used as starting materials are known or can be prepared by methods known from the literature [for example D. Borrmann, “Um GmbH von Diketen mit mecanicen, Phenolen und Mercaptanen”, in Houben-Weyl, Methoden der organischen Chemie, Vol. VII/4, 230 ff (1968); Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem. 43, 2087 (1978)].
- All process steps are carried out at atmospheric pressure and in a temperature range of from 0° C. to 130° C., preferably from 20° C. to 100° C.
- the compounds of the formula (VIII) are known per se or can be prepared by known processes similarly to Example I and II by reacting pyridines of the general formula (IX) R 5 —H (IX) in which the hydrogen is ortho to the nitrogen and in which R 5 is as defined above, initially at from 50 to 150° C., preferably at 100° C., in H 2 O 2 /glacial acetic acid to give the corresponding N-oxides, followed by a reaction with trimethylsilyl cyanide (TMSCN) by processes known from the literature in the abovementioned inert solvents, preferably acetonitrile, THF, toluene at room temperature or at reflux temperature, if appropriate with addition of bases such as triethylamine or DBU, or by replacing, in compounds of the formula (X)
- TMSCN trimethylsilyl cyanide
- Y and Z represent the substitution radicals of the pyridyl ring mentioned under R 5 , the chlorine with cyanide, using cyanides, such as potassium cyanide or copper cyanide, or by reacting, in the case where R 5 represents difluoropyridyl, compounds of the formula (XI)
- Y′ and Z′ are identical or different, and each represents chlorine or bromine, with alkali metal or ammonium fluorides, preferably potassium fluoride, by processes known from the literature, in polar solvents, such as, for example, polyglycols and ethers thereof, DMSO or sulpholane, if appropriate with addition of phase-transfer catalysts, in a halogen-fluorine exchange reaction.
- polar solvents such as, for example, polyglycols and ethers thereof, DMSO or sulpholane, if appropriate with addition of phase-transfer catalysts, in a halogen-fluorine exchange reaction.
- the invention also relates to a compound of the formula below from which the corresponding amidine intermediate can be prepared in the manner described in the examples:
- the antiviral activity of the compounds according to the invention was investigated following the methods described by Sells et al. (M. A. Sells, M.-L. Chen, and G. Acs (1987) Proc. Natl. Acad. Sci. 84, 1005-1009) and Korba et al. (B. E. Korba and J. L. Gerin (1992) Antiviral Research 19, 55-70).
- the antiviral tests were carried out in 96-well microtitre plates. Only growth medium and HepG2.2.15 cells were added to the first vertical row of the plate. This row served as virus control.
- test compounds 50 mM were initially dissolved in DMSO, and further dilutions were prepared in the growth medium of HepG2.2.15.
- the compounds according to the invention usually in a test concentration of 100 ⁇ M (1st test concentration), were in each case pipetted into the second vertical test row of the microtitre plate and subsequently diluted, by a factor of 2 each time, up to 2 10 -fold, using growth medium plus 2% of foetal calf serum (volume 25 ⁇ l).
- 225 ⁇ l of a HepG2.2.15 cell suspension (5 ⁇ 10 4 cells/ml) in growth medium plus 2% foetal calf serum were then added to each well of the microtitre plate.
- test batch was incubated at 37° C., 5% CO 2 , for 4 days.
- the supernatant was subsequently siphoned off and discarded, and 225 ⁇ l of freshly prepared growth medium were added to the wells. Once more, the compounds according to the invention were added, in each case as a solution 10-fold-concentrated, in a volume of 25 ⁇ l. The batches were incubated for another 4 days.
- the HepG2.2.15 cells were examined under the light microscope or by biochemical detection methods (for example Alamar Blue staining or Trypan Blue staining) for cytotoxic changes.
- the supernatants were subsequently harvested and, by means of reduced pressure, siphoned onto 96-well dot blot chambers covered with a nylon membane (in accordance with the specifications of the manufacturer).
- Substance-induced cytotoxic or cytostatic changes in the HepG2.2.15 cells were determined as changes in the cell morphology, for example under a light microscope. Such substance-induced changes of the HepG2.2.15 cells in comparison with untreated cells could be observed, for example, as cell lysis, vacuolization or changed cell morphology.
- 50% cytotoxicity (Tox. ⁇ 50) means that 50% of the cells have a morphology which is similar to the corresponding cell control.
- the compatibility of some of the compounds according to the invention was additionally tested on other host cells, such as, for example, HeLa cells, primary peripheral human blood cells or transformed cell lines, such as H-9 cells.
- the supernatants of the HepG2.2.15 cells were denatured (1.5 M NaCl/0.5 N NaOH), neutralized (3 M NaCl/0.5 M Tris HCl, pH 7.5) and washed (2 ⁇ SSC). By incubation of the filters at 120° C. for 2-4 hours, the DNA was subsequently baked onto the membrane.
- the viral DNA of the treated HepG2.2.15 cells on the nylon filters was usually detected using non-radioactive digoxygenin-labelled hepatitis B-specific DNA probes which were in each case in accordance with the specifications of the manufacturer labelled with digoxygenin, purified and used for hybridization.
- the prehybridization and hybridization was carried out in 5 ⁇ SSC,1 ⁇ blocking reagent, 0.1% N-lauroylsarcosine, 0.02% SDS and 100 ⁇ g of DNA from herring sperm.
- the prehybridization was carried out at 60° C. for 30 minutes and the specific hybridization was carried out using 20 to 40 ⁇ g/ml of the digoxygenated denatured HBV-specific DNA (14 hours, 60° C.). The filters were subsequently washed.
- the filters were washed and prehybridized in a blocking agent (in accordance with the specifications of the manufacturer). They were subsequently hybridized for 30 minutes using an anti-DIG antibody linked to alkaline phosphatase. After a washing step, the substrate of alkaline phosphatase, CSPD, was added, incubated with the filters for 5 minutes, subsequently wrapped in plastic film and incubated at 37° C. for a further 15 minutes. The chemiluminescence of the Hepatitis B-specific DNA signals was visualized by exposition of the filters on an X-ray film (incubation, depending on the signal strength: 10 minutes to 2 hours).
- the half-maximum inhibitory concentration (IC-50, inhibitory concentration 50%) was determined as the concentration at which the hepatitis B-specific band was reduced by 50% in comparison with an untreated sample by the compound according to the invention.
- the treatment of the hepatitis B virus-producing HepG2.2.15 cells with the compounds according to the invention resulted in a reduction of viral DNA in the cell culture supernatant, the viral DNA being released by the cells into the cell culture supernatant in the form of virions.
- the compounds according to the invention have a novel unforeseeable and useful action against viruses. Surprisingly, they are antivirally active against hepatitis B (HBV) and are therefore suitable for treating virus-induced diseases, in particular acute and chronically persisting HBV virus infections.
- HBV hepatitis B
- a chronic viral disease caused by HBV can lead to clinical pictures of various gravity; as is known, chronic hepatitis B virus infection frequently results in cirrhosis of the liver and/or hepatocellular carcinoma.
- the treatment of acute and chronic virus infections which may lead to an infectious hepatitis, for example infections with hepatitis B viruses.
- Particular preference is given to the treatment of chronic hepatitis B infections and the treatment of acute hepatitis B virus infection.
- the present invention encompasses pharmaceutical formulations which, in addition to non-toxic inert pharmaceutically acceptable excipients, contain one or more compounds of the formulae (I), (Ia) or of Table A or which comprise one or more active compounds of the formulae (I), (Ia) and (Ib), and also encompasses processes for producing these formulations.
- the active compounds of the formulae (I), (Ia) and (Ib) should be present in a concentration of approximately 0.1-99.5% by weight, preferably of approximately 0.5-95% by weight of the total mixture.
- compositions may, in addition to the compounds of the formulae (I), (Ia) and (Ib), also contain further pharmaceutically active compounds.
- the abovementioned pharmaceutical formulations are produced in a customary manner by known methods, for example by mixing the active compound(s) with the excipient(s).
- the active compound(s) in total amounts of from approximately 0.5 to approximately 500, preferably 1-100 mg/kg of body weight per 24 hours, if appropriate in the form of several individual doses, to obtain the desired results.
- An individual dose preferably contains the active compound(s) in amounts of from approximately 1 to approximately 80, in particular 1-30 mg/kg of body weight.
- Example IV 50 g (0.29 mol) of 3,5-dichloropyridine-2-carbonitrile (Example IV), 33.6 g (0.58 mol) of potassium fluoride and 10 g of polyethylene glycol 8000 are admixed with 125 ml of DMSO and heated at 160° C. for 30 min. After cooling, the product, together with the DMSO, is distilled off under high vacuum, and the distillate is poured into water, extracted with toluene and dried over Na 2 SO 4 . The product is reacted further as a solution in toluene.
- the mixture is concentrated using a rotary evaporator and the residue is dissolved in 500 ml of CH 2 Cl 2 /MeOH (9:1) and once more filtered off with suction from inorganic salts.
- the mixture is concentrated using a rotary evaporator, giving 23.6 g (39.1%) of 3,5-difluoro-2-pyridinecarboximidamide as hydrochloride (m.p.: 183° C.).
- the aqueous phase is made alkaline using dilute ammonia solution, extracted with ethyl acetate, and the organic phase is washed with H 2 O, dried and concentrated. The residue is dissolved in a little ether and crystallized. The crystals are filtered off with suction, washed with ether and dried at 60° C. under reduced pressure.
- the mixture is cooled to room temperature and then filtered off with suction from inorganic salts and concentrated.
- the residue is taken up in 30 ml of 1N HCl and 35 ml of ethyl acetate, and the phases are separated.
- the ethyl acetate phase is re-extracted once using 30 ml of 1N HCl.
- the combined aqueous phases are extracted three times with 10 ml of diethyl ether each time.
- the aqueous phase is made alkaline using NaOH and extracted with ethyl acetate.
- the organic phases are dried over Na 2 SO 4 and concentrated.
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Abstract
Description
- R1 represents phenyl, furyl, thienyl, triazolyl, pyridyl, cycloalkyl having 3 to 6 carbon atoms or represents radicals of the formulae
- where the abovementioned ring systems are optionally mono- or polysubstituted by identical or different substituents selected from the group consisting of halogen, trifluoromethyl, nitro, cyano, trifluoromethoxy, carboxyl, hydroxyl, (C1-C6)-alkoxy, (C1-C6)-alkoxycarbonyl and (C1-C6)-alkyl, which for its part may be substituted by aryl having 6 to 10 carbon atoms or halogen, and/or the ring systems mentioned are optionally substituted by groups of the formulae —S—R6, NR7R8, CO—NR9R10, SO2—CF3, and -A-CH2—R11,
- in which
- R6 represents phenyl which is optionally substituted by halogen,
- R7, R8, R9 and R10 are identical or different, and each represents hydrogen, phenyl, hydroxyl-substituted phenyl, hydroxyl, (C1-C6)-acyl or (C1-C6)-alkyl, which for its part may be substituted by hydroxyl, (C1-C6)-alkoxycarbonyl, phenyl or hydroxyl-substituted phenyl,
- A represents a radical O, S, SO or SO2,
- R11 represents phenyl which is optionally mono- to polysubstituted by identical or different substituents selected from the group consisting of halogen, nitro, trifluoromethyl, (C1-C6)-alkyl and (C1-C6)-alkoxy,
- R2 represents a radical of the formula —XR12 or —NR13R14,
- in which
- X represents a bond or oxygen,
- R12 represents hydrogen, straight-chain or branched (C1-C6)-alkoxycarbonyl or a straight-chain, branched or cyclic saturated or unsaturated (C1-C8)-hydrocarbon radical which optionally contains one or two identical or different hetero chain members from the group consisting of O, CO, NH, —NH—(C1-C4)-alkyl, —N—((C1-C4)-alkyl)2, S and SO2 and which is optionally substituted by halogen, nitro, cyano, hydroxyl, aryl having 6 to 10 carbon atoms or aralkyl having 6 to 10 carbon atoms, heteroaryl or a group of the formula —NR15R16,
- in which
- R15 and R16 are identical or different, and each represents hydrogen, benzyl or (C1-C6)-alkyl,
- R13 and R14 are identical or different, and each represents hydrogen, (C1-C6)-alkyl or cycloalkyl having 3 to 6 carbon atoms,
- R3 represents hydrogen, amino or
- represents a radical of the formula
- represents formyl, cyano, trifluoromethyl or pyridyl, or
- represents a straight-chain, branched or cyclic saturated or unsaturated hydrocarbon radical having up to 8 carbon atoms which is optionally mono- or polysubstituted by identical or different substituents from the group consisting of aryloxy having 6 to 10 carbon atoms, azido, cyano, hydroxyl, darboxyl, (C1-C6)-alkoxycarbonyl, a 5- to 7-membered heterocyclic ring, (C1-C6)-alkylthio and (C1-C6)-alkoxy, which for its part may be substituted by azido or amino,
- and/or is substituted by triazolyl, which for its part may be substituted up to 3 times by (C1-C6)-alkoxycarbonyl,
- and/or may be substituted by groups of the formulae —OSO2—CH3 or (CO)a—NR17R18,
- in which
- a represents a number 0 or 1,
- R17 and R18 are identical or different, and each represents hydrogen or aryl, aralkyl having 6 to 10 carbon atoms,
- or represents (C1-C6)-alkyl which is optionally substituted by (C1-C6)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, (C1-C6)-alkyl and (C1-C6)-alkoxy,
- or (C1-C6)-alkyl is optionally substituted by groups of the formulae NH—CO—CH3 or NH—CO—CF3,
- or
- R17 and R18 together with the nitrogen atom form a morpholine, piperidinyl or pyrrolidinyl ring,
- or
- R3 represents phenyl which is optionally substituted by methoxy,
- or
- R2 and R3 together form a radical of the formula
- R4 represents hydrogen, (C1-C4)-alkyl, (C2-C4)-alkenyl, benzoyl or represents acyl having 2 to 6 carbon atoms,
- R5 represents pyridyl which is substituted up to 3 times by identical or different substituents from the group consisting of halogen, hydroxyl, cyano, trifluoromethyl, (C1-C6)-alkoxy, (C1-C6)-alkyl, (C1-C6)-alkylthio, carbalkoxy, (C1-C6)-acyloxy, amino, nitro, mono- and (C1-C6)-dialkylamino,
and salts thereof.
- R1 represents phenyl, furyl, thienyl, pyridyl, cyclopentyl or cyclohexyl or represents radicals of the formulae
- where the abovementioned ring systems are optionally mono- or disubstituted by identical or different substituents selected from the group consisting of halogen, trifluoromethyl, nitro, SO2—CF3, methyl, cyano, trifluoromethoxy, amino, hydroxyl, carboxyl, methoxycarbonyl and radicals of the formulae —CO—NH—CH2—C(CH3)3, —CO—NH(CH2)2OH, —CO—NH—CH2—C6H5, —CO—NH—C6H5, —CO—NH-(pOH)—C6H4, —O—CH2—C6H5 or —S-pCl—C6H4,
- R2 represents a radical of the formula —XR12 or —NR13R14,
- in which
- X represents a bond or an oxygen atom,
- R12 represents hydrogen, (C1-C4)-alkenyl, (C1-C4)-alkoxycarbonyl or (C1-C4)-alkyl which are optionally substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula —NR15R16,
- in which
- R15 and R16 are identical or different, and each represents hydrogen, benzyl or (C1-C4)-alkyl,
- R13 and R14 are identical or different, and each represents hydrogen, (C1-C4)-alkyl or cyclopropyl,
- R3 represents hydrogen, amino or a radical of the formula
- or
- represents formyl, cyano, trifluoromethyl, cyclopropyl or pyridyl, or represents (C1-C4)-alkyl which is optionally substituted by halogen, (C1-C4)-alkoxycarbonyl, hydroxyl or by triazolyl, which for its part may be substituted up to 3 times by (C1-C4)-alkoxycarbonyl,
- and/or alkyl is optionally substituted by groups of the formulae —OSO2—CH3 or (CO)a—NR17R18,
- in which
- a represents a number 0 or 1,
- R17 and R18 are identical or different, and each represents hydrogen, phenyl or benzyl, or
- represents C1-C4-alkyl which is optionally substituted by (C1-C4)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono- or polysubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, (C1-C4)-alkyl and (C1-C4)-alkoxy,
- and/or (C1-C4)-alkyl is optionally substituted by radicals of the formulae —NH—CO—CH3 or —NH—CO—CF3,
- or
- R17 and R18 together with the nitrogen atom form a morpholine, piperidinyl or pyrrolidinyl ring,
- or
- R3 represents phenyl which is optionally substituted by methoxy,
- or
- R2 and R3 together form a radical of the formula
- R4 represents hydrogen, methyl, benzoyl or acetyl,
- R5 represents pyridyl which is substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, (C1-C4)-alkoxy and (C1-C4)-alkyl,
and salts thereof.
- R1 represents phenyl, furyl, thienyl, pyridyl, cyclopentyl, cyclohexyl or represents radicals of the formulae
- where the abovementioned ring systems are optionally substituted up to 2 times by identical or different substituents selected from the group consisting of fluorine, chlorine, bromine, iodine, hydroxyl, trifluoromethyl, nitro, SO2—CF3, methyl, cyano, amino, trifluoromethoxy, carboxyl, methoxycarbonyl and radicals of the formulae —CO—NH—CH2—C(CH3)3, —CO—NH(CH2)2OH, —CO—NH—CH2—C6H5, —CO—NH—C6H5, —CO—NH-(pOH)—C6H4, —O—CH2—C6H5 or —S-pCl—C6H4,
- R2 represents a radical of the formula —XR12 or —NR13R14,
- in which
- X represents a bond or an oxygen atom,
- R12 represents hydrogen, (C1-C3)-alkenyl, (C1-C4)-alkoxycarbonyl or (C1-C4)-alkyl which are optionally substituted by pyridyl, cyano, phenoxy, benzyl or by a radical of the formula —NR15R16,
- in which
- R15 and R16 are identical or different, and each represents hydrogen or methyl,
- R13 and R14 are identical or different, and each represents hydrogen, (C1-C3)-alkyl or cyclopropyl,
- R3 represents hydrogen, amino or represents a radical of the formula
- or
- represents formyl, cyano, trifluoromethyl, cyclopropyl or pyridyl, or
- represents (C1-C4)-alkyl which is optionally substituted by fluorine, chlorine, (C1-C3)-alkoxycarbonyl, hydroxyl or by triazolyl, which for its part may be substituted up to 3 times by (C1-C3)-alkoxycarbonyl,
- and/or alkyl is optionally substituted by groups of the formulae —OSO2—CH3 or (CO)n—NR17R18,
- in which
- a represents a number 0 or 1,
- R17 and R18 are identical or different, and each represents hydrogen, phenyl or benzyl, or
- represents (C1-C3)-alkyl which is optionally substituted by (C1-C3)-alkoxycarbonyl, hydroxyl, phenyl or benzyl, where phenyl or benzyl are optionally mono- or disubstituted by identical or different substituents from the group consisting of hydroxyl, carboxyl, (C1-C3)-alkyl and (C1-C3)-alkoxy,
- and/or (C1-C4)-alkyl is optionally substituted by radicals of the formulae —NH—CO—CH3 or —NH—CO—CF3,
- or
- R17 and R18 together with the nitrogen atom form a morpholine, piperidinyl or pyrrolidinyl ring,
- or
- R3 represents phenyl which is optionally substituted by methoxy,
- or
- R2 and R3 together form a radical of the formula
- R4 represents hydrogen, methyl, benzoyl or acetyl,
- R5 represents pyridyl which is substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, (C1-C3)-alkoxy and (C1-C3)-alkyl,
and salts thereof.
- in which
- R1 represents phenyl which is optionally substituted up to 2 times by identical or different substituents from the group consisting of fluorine, chlorine, bromine, iodine, methyl and nitro,
- R2 represents —XR12 in which X represents oxygen and R12 represents straight-chain or branched alkyl having up to 4 carbon atoms,
- R3 represents methyl, ethyl or cyclopropyl,
- or
- R2 and R3 together form a radical of the formula
- R4 represents hydrogen or acetyl,
- and
- R5 represents pyridyl which is substituted up to two times by identical or different substituents from the group consisting of fluorine and chlorine,
and salts thereof.
R1—CHO (II)
in which
- R1 is as defined above,
with amidines or their hydrochlorides of the formula (III)
- R5 is as defined above,
and compounds of the general formula (IV)
R3—CO—CH2—CO—R2 (IV)
in which - R2 and R3 are each as defined above,
if appropriate in the presence of inert organic solvents, with or without addition of base or acid,
or
- R1, R2 and R3 are each as defined above,
with amidines of the general formula (III)
- R5 is as defined above,
if appropriate in the presence of inert organic solvents at temperatures between 20° C. and 150° C., with or without addition of base or acid,
or
R1—CHO (II)
in which
- R1 is as defined above,
with compounds of the general formula (VI)
- R2 and R3 are each as defined above,
and amidines of the general formula (III) as described above,
or
- R5 is as defined above,
and - R1 represents (C1-C4)-alkyl,
in the presence of ammonium salts.
R5—CN (VIII)
in which
- R5 is as defined above,
in the customary way via the imino ethers and finally with ammonium chloride in methanol [cf. in this context W. K. Fife, Heterocycles 22, 93-96 (1984); T. Sakamoto, S. Kaneda, S. Nishimura, H. Yamanaka, Chem. Pharm. Bull. 33, 565-571 (1986)] or other processes known from the literature, such as, for example, Garigipati, Tetrahedron Lett. 1990, pp. 1969-1972, Boere et al., J. Organomet. Chem. 1987, 331, 161, Caton et al., J. Chem. Soc. 1967, 1204.
and its salts from which preferred end products can be prepared. With respect to the salts of this compound, reference is made to the abovementioned acid addition salts and in particular to the hydrochloride. This compound is prepared as described in the examples, and, in this respect, reference is also made to the reaction scheme shown below.
R5—H (IX)
in which the hydrogen is ortho to the nitrogen and in which R5 is as defined above, initially at from 50 to 150° C., preferably at 100° C., in H2O2/glacial acetic acid to give the corresponding N-oxides, followed by a reaction with trimethylsilyl cyanide (TMSCN) by processes known from the literature in the abovementioned inert solvents, preferably acetonitrile, THF, toluene at room temperature or at reflux temperature, if appropriate with addition of bases such as triethylamine or DBU,
or by replacing, in compounds of the formula (X)
in which Y and Z represent the substitution radicals of the pyridyl ring mentioned under R5, the chlorine with cyanide, using cyanides, such as potassium cyanide or copper cyanide,
or by reacting, in the case where R5 represents difluoropyridyl, compounds of the formula (XI)
in which Y′ and Z′ are identical or different, and each represents chlorine or bromine, with alkali metal or ammonium fluorides, preferably potassium fluoride, by processes known from the literature, in polar solvents, such as, for example, polyglycols and ethers thereof, DMSO or sulpholane, if appropriate with addition of phase-transfer catalysts, in a halogen-fluorine exchange reaction.
TABLE 1 | |||
Example | |||
No.: | Structure | m.p. [° C.] | Rf |
2 |
|
121-123 | — |
3 |
|
>120 | — |
4 |
|
152-53 | — |
5 |
|
142-143 | — |
6 |
|
142-143 | — |
7 |
|
139-140 | — |
8 |
|
173-175 | — |
9 |
|
174-175 | — |
10 |
|
127-129 | — |
11 |
|
133-134 | — |
12 |
|
110-111 | — |
13 |
|
222decomposition | — |
14 |
|
140-142 | — |
15 |
|
165-167 | — |
16 |
|
180-182 | — |
17 |
|
148-149 | — |
18 |
|
121-123 | — |
19 |
|
151-153 | — |
20 |
|
117-119(−)-enantiomerof Example 4 | — |
21 |
|
138-140 | — |
22 |
|
163-165 | — |
23 |
|
124-126 | — |
24 |
|
123-125 | — |
25 |
|
145-146 | — |
26 |
|
120-122 | — |
27 |
|
144-146 | — |
28 |
|
135-137 | — |
29 |
|
143-144 | — |
30 |
|
156-157 | — |
31 |
|
134-135 | — |
32 |
|
247-248 | — |
33 |
|
119-120(−)-enantiomer | — |
34 |
|
129-130° C.(−) enantiomer | — |
35 |
|
(−) enantiomerof Ex. 19 | — |
36 |
|
126-127 | — |
37 |
|
156-158 | — |
38 |
|
162-163 | — |
39 |
|
167-169 | — |
40 |
|
129-130 | — |
41 |
|
163-164 | — |
42 |
|
120-122 | — |
43 |
|
103-104 | — |
44 |
|
210-212 | — |
45 |
|
132-133° C. | — |
46 |
|
95-96° C. | — |
47 |
|
154-155° C. | — |
48 |
|
131-132° C. | — |
49 |
|
137-138° C. | — |
50 |
|
184-186° C. | — |
51 |
|
133-134° C. | — |
52 |
|
135-136° C. | — |
53 |
|
131° C. | — |
54 |
|
amorphous | 0.17 (cyclo-hexane/ethylacetate =7:3) |
55 |
|
124° C. | — |
56 |
|
141° C. | — |
57 |
|
132° C. | — |
58 |
|
amorphous | 0.14 (cyclo-hexane/-ethylacetate =7:3) |
59 |
|
amorphous | 0.23 (cyclo-hexane/ethylacetate =7:3) |
60 |
|
126° C. | — |
TABLE 2 | |||
Example No.: | Structure | [M + H] | MS ES + |
61 |
|
117° C.(ethanol)(−)-enantiomer | — |
62 |
|
amorphous(−)-enantiomer | 0.23 (cyclohexane/ethylacetate = 7:3) |
63 |
|
amorphous | 0.36 (toluene/-ethylacetate = 1:1)(−)-enantiomer |
64 |
|
119-120° C.(−)-enantiomer | |
65 |
|
159° C. | — |
66 |
|
154° C. | — |
67 |
|
amorphous | 0.33 (toluene/-ethylacetate = 1:1)(−)-enantiomer |
68 |
|
amorphous | 0.30 (cyclohexane/ethylacetate = 7:3) |
69 |
|
152° C. | 0.35 (cyclohexane/ethylacetate = 7:3) |
70 |
|
amorph | 0.33 (toluene/-ethylacetate = 1:1) |
71 |
|
91-93° C.(−) enantiomer | |
72 |
|
amorphous | 0.20 (cyclohexane/ethylacetate = 1:1) |
73 |
|
amorphous | 0.27 (CH2Cl2/MeOH = 95:5) |
74 |
|
362 | |
75 |
|
376 | |
76 |
|
371 | |
77 |
|
372 | |
78 |
|
385 | |
79 |
|
408 | |
80 |
|
421 | |
81 |
|
453 | |
82 |
|
466 | |
83 |
|
425 | |
84 |
|
371 | |
m.p. [° C.] = melting point in degrees Celsius |
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